Using fMRI to evaluate the effects of milnacipran on central pain processing in patients with fibromyalgia.

Background In recent years, the prescription of serotonin-noradrenalin reuptake inhibitors (SNRIs) for treatment of fibromyalgia (FM) has increased with reports of their efficacy. The SNRI milnacipran is approved by the U.S. Food and Drug Administration (FDA) for treatment of FM, yet, the mechanisms by which milnacipran reduces FM symptoms are unknown. A large number of neuroimaging studies have demonstrated altered brain function in patients with FM but the effect of milnacipran on central pain processing has not been investigated. The primary objective of this study was to assess the effect of milnacipran on sensitivity to pressure-evoked pain in FM. Secondary objectives were to assess the effect of milnacipran on cerebral processing of pressure-evoked pain using fMRI and the tolerability and safety of milnacipran 200 mg/day in FM. Methods 92 patients were randomized to either 13-weeks milnacipran treatment (200 mg/day) or placebo in this double-blind, placebo-controlled multicenter clinical trial. Psychophysical measures and functional MRI (fMRI) assessments were performed before and after treatment using a computer-controlled pressure-pain stimulator. Here, we present the results of several a priori defined statistical analyses. Results Milnacipran-treated patients displayed a trend toward lower pressure-pain sensitivity after treatment, compared to placebo, and the difference was greater at higher pain intensities. A single group fMRI analysis of milnacipran-treated patients indicated increased pain-evoked brain activity in the caudatus nucleus, anterior insula and amygdala after treatment, compared to before treatment; regions implicated in pain inhibitory processes. A 2 × 2 repeated measures fMRI analysis, comparing milnacipran and placebo, before and after treatment, showed that milnacipran-treated patients had greater pain-evoked activity in the precuneus/posterior cingulate cortex after treatment; a region previously implicated in intrinsic brain function and FM pathology. This finding was only significant when uncorrected for multiple comparisons. The safety analysis revealed that patients from both treatment groups had treatment-emergent adverse events where nausea was the most common complaint, reported by 43.5% of placebo patients and 71.7% of milnacipran-treated patients. Patients on milnacipran were more likely to discontinue treatment because of side effects. Conclusions Our results provide preliminary indications of increased pain inhibitory responses in milnacipran-treated FM patients, compared to placebo. The psychophysical assessments did not reach statistical significance but reveal a trend toward higher pressure-pain tolerance after treatment with milnacipran, compared to placebo, especially for higher pain intensities. Our fMRI analyses point toward increased activation of the precuneus/posterior cingulum in patients treated with milnacipran, however results were not corrected for multiple comparisons. The precuneus/posterior cingulum is a key region of the default mode network and has previously been associated with abnormal function in FM. Future studies may further explore activity within the default mode network as a potential biomarker for abnormal central pain processing. Implications The present study provides novel insights for future studies where functional neuroimaging may be used to elucidate the central mechanisms of common pharmacological treatments for chronic pain. Furthermore, our results point toward a potential mechanism for pain normalization in response to milnacipran, involving regions of the default mode network although this finding needs to be replicated in future studies.

[Comparative pharmacokinetics of piperacillin in young and elderly subjects]. / Pharmacocinétique comparative de la pipéracilline chez le sujet jeune et le sujet âgé.

One single 4 g dose of piperacillin was administered by intravenous infusion over 30 min to 15 patients aged from 66 to 90 years (mean +/- s.e.m.: 79.8 +/- 2.0 years); the patients mean weight was 53 +/- 4 kg. Fifteen samples of blood were withdrawn from each subject. Plasma piperacillin levels were measured by high performance liquid chromatography with detection in ultraviolet light at 214 nm. Mean plasma piperacillin concentrations in elderly subjects, measured 0.5, 2 and 12 h after dosing, were 168.5 +/- 15.7, 79.9 +/- 11.5 and 1.72 +/- 0.69 microgram.ml-1, as against 146.8 +/- 10.6, 35.5 +/- 3.9 and 0.212 +/- 0.040 microgram.ml-1 in healthy young adults. Plasma piperacillin concentrations versus time curves obtained after the infusion was discontinued were bi-exponential, with half-lives T1/2 (lambda 1) and T1/2 (lambda 2) of 0.65 +/- 0.11 and 1.72 +/- 0.09 h respectively; the corresponding figures in young adults were 0.59 +/- 0.03 and 1.81 +/- 0.13 h respectively). In elderly subjects the mean total clearance of piperacillin (ClT = 2.90 +/- 0.25 ml.min-1.kg-1) was reduced by 15% (NS) and the volume of distribution during steady state (Vdss = 0.337 +/- 0.027 L.kg-1) was increased by 43% (P less than 0.001). As a result, the mean time of piperacillin stay in the body (MRS = Vdss/Cl) was practically doubled in elderly subjects (2.09 +/- 0.15 h as against 1.15 +/- 0.04 h in young adults (P less than 0.01).

Trifluoperazine antagonizes postsynaptic alpha 1-but not alpha 2-adrenoceptor-mediated pressor responses in the rat.

The specificity of the alpha-adrenergic blockade by trifluoperazine was tested in pithed rats. Trifluoperazine reduced the pressor effects of (-)-noradrenaline. The log dose-response curve to methoxamine, an alpha 1-agonist, was shifted to the right whereas the vasopressor responses to BHT-920, an alpha 2-agonist, were unaffected by trifluoperazine. It was concluded that trifluoperazine acts as a peripheral vascular alpha 1-antagonist in the rat.